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Potassium Channels in Epilepsy

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Potassium Channels in Epilepsy Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Potassium Channels in Epilepsy Ru¨diger Ko¨hling and Jakob Wolfart Oscar Langendorff Institute of Physiology, University of Rostock, Rostock 18057, Germany Correspondence: [email protected] This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dy- namic, aggravating, or adaptive transcriptional and posttranslational alterations. In these cases, it often remains elusive whether the alteration is causal or merely incidental. With 80 potassium channel types, of which 10% are known to be associated with epilepsies (in humans) or a seizure phenotype (in animals), if genetically mutated, a comprehensive review is a challenging endeavor. This goal may seem all the more ambitious once the data on posttranslational alterations, found both in human tissue from epilepsy patients and in chronic or acute animal models, are included. We therefore summarize the literature, and expand only on key findings, particularly regarding functional alterations found in patient brain tissue and chronic animal models. INTRODUCTION TO POTASSIUM evolutionary appearance of voltage-gated so- CHANNELS dium (Nav)andcalcium (Cav)channels, Kchan- nels are further diversified in relation to their otassium (K) channels are related to epilepsy newer function, namely, keeping neuronal exci- Psyndromes on many different levels, ranging tation within limits (Anderson and Greenberg from direct control of neuronal excitability and 2001; Hille 2001). Structurally, K channels con- homeostasis of ion milieu to indirect effects sist of transmembrane (TM) protein elements www.perspectivesinmedicine.org via metabolism. We discuss K channels and similar to the Cav and Nav channels and the cy- their relevance to epilepsy (1), in particular, clic nucleotide-regulated channels, with which with respect to genetic alterations in humans the K channels can be grouped into a superfam- (2) and animal models (3), as well as acquired ily of “voltage-gated-like” ion channels (Yu et al. in humans (4) and animal models (5), and we 2005; Alexander et al. 2013). The K-channel highlight recent mechanisms on K channels in family is by far the largest: ,70 human genes antiepileptic drug (AED) research (6). encoding for different a subunits have been dis- Probably, all biological cells have K chan- covered since the beginning of K-channel clon- nels; they are crucial for all transmembrane ing (Fig. 1) (Coetzee et al. 1999; Goldstein et al. transport mechanisms. In addition, since the 2005; Gutman et al. 2005; Kubo et al. 2005; Wei Editors: Gregory L. Holmes and Jeffrey L. Noebels Additional Perspectives on Epilepsy: The Biology of a Spectrum Disorder available at www.perspectivesinmedicine.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a022871 Cite this article as Cold Spring Harb Perspect Med 2016;6:a022871 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press R. Ko¨hling and J. Wolfart et al. 2005; Trimmer 2015). With the formation channels, behave similarly to Kir channels with of heteromers, modulating b subunits, and dif- high [K]o. Under physiological conditions, ferential expression, thousands of different K most of the K2P channels are open rectifiers— channels are possible. Four a subunits are nec- they conduct mainly outward K currents (Gold- essary to build a functional K channel (Fig. 1). stein et al. 2001). In addition, K2P channels in- The a subunits are differentiated according to tegrate other signals, as in the case of TWIK- whether they consist of 2, 4, or 6TM domains. related acid-sensitive (TASK) channels, which More common are functionally defined names are sensitive to external pH changes (Lesage such as “inward rectifier” K (Kir) channels for and Lazdunski 2000; Goldstein et al. 2001). 2TM channels, “leak two pore domain” K From the human genetics point of view, there (K2P) channels for 4TM, and “voltage-gated” is little association between K2P channels and K(Kv) channels for 6TM (Fig. 1). epilepsy, but there are data on K2P channels in seizure models (see below). Note that there is no simple correlation between the func- Inward Rectifier Potassium Channels tional (historical) naming and the later clas- As the name suggests, Kir channels conduct in- sification according to a sequence relationship ward current better than outward current; re- (TWIK1, K2P1.1; TWIK2, K2P6.1; TASK1, sponsible for this is a magnesium or polyamine K2P3.1; TASK2, K2P5.1). block at depolarized potentials (Kubo et al. 2005). However, under physiological condi- Voltage-Gated Potassium Channels tions, the resting membrane potential (Vrest) of neurons is unlikely to become more negative The largest ion channel group is the Kv channel than the equilibrium potential of K ions (EK); family, which consists of 12 Kv (sub-) families. the functional importance of Kir channels, such The founding group, the shaker-related Kv1 as the “classic leak Kir” channels of the Kir2 channel family was named after the mus- group, is to provide the basic K current main- cle seizure phenotype of the corresponding taining Vrest (Stanfield et al. 2002). Some of fly mutant (Pongs et al. 1988). Subsequently the Kir channels are coupled to and modulated discovered groups were classified as shab-related by G-proteins, among them, Kir3 (Girk) chan- (Kv2), shaw-related (Kv3), and shal-related (Kv4) nels. In glial cells, Vrest can become more nega- (Coetzee et al. 1999; Gutman et al. 2005). tive than EK during and because of spatial buf- From the functional point of view, all Kv chan- fering of extracellular potassium concentrations nels are activated by depolarization and deac- ([K]o), in particular via Kir4 channels (Butt and tivated by repolarization, both relatively fast. www.perspectivesinmedicine.org Kalsi 2006). Thus, Kir4.1 channels are found Inactivation occurs when the open channel is exclusively in glial cells (Higashi et al. 2001). occluded via intracellular “ball domains” dur- The Kir6(KAT P) channels are coupled to the in- ing prolonged depolarization. When inactiva- tracellular energy supply; when ATP levels are tion is fast (i.e., visible within tens of millisec- high, Kir6 channels are closed, whereas during onds), it is called “A-type current” after the prolonged action potential (AP) firing Kir6 initial description in the gastropod Anisodoris channels will eventually contribute to resetting (Connor and Stevens 1971). Such ball domains Vrest (Isomoto et al. 1997). canbepartofthechannellikeinthecaseoftheA- type subunits Kv1.4, Kv3.4, and Kv4, or they are part of an accessory unit, as in the case of the Two Pore Domain Potassium Channels Kvb1.1 (KCNMB1), which confers the A-type Also K2P channels contribute to leak cur- phenotype on the Kv1 subunits it assembles rent important for Vrest (Lesage and Lazdunski with (Rettig et al. 1992, 1994). The term “delayed 2000; Goldstein et al. 2001). Hence, functional- rectifier” outward current (IK) describes the de- ly, some of these, for example, the “tandem of P layed activation relative to the ultrafast (msec domains in weak inward rectifier (TWIK)” K range) activation of Nav currents (Hodgkin and 2 Cite this article as Cold Spring Harb Perspect Med 2016;6:a022871 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Potassium Channels in Epilepsy Kir1.1/KCNJ1(1) 2TM, Kir, KCNJ K 2.1/KCNJ2 , K 2.2/KCNJ12 , K 2.3/KCNJ4 , K 2.4/KCNJ14 ir (3) ir (0) ir (0) ir (0) I α Kir3.1/KCNJ3(4), Kir3.2/KCNJ6(6), Kir3.3/KCNJ9(2), Kir3.4/KCNJ5(0) α α Kir4.1/KCNJ10(35), Kir4.2/KCNJ15(0) α Kir5.1/KCNJ16(3) V Kir6.1/KCNJ8(1), Kir6.2/KCNJ11(36) Kir7.1/KCNJ13(1) K2P1.1/KCNK1(1) K2P9.1/KCNK9(6) 4TM, K2P, KCNK K2P2.1/KCNK2(0) K2P10.1/KCNK10(1) I α K2P3.1/KCNK3(1) K2P12.1/KCNK12(0) α α K2P4.1/KCNK4(0) K2P13.1/KCNK13(0) α V K2P5.1/KCNK5(0) K2P15.1/KCNK15(0) K2P6.1/KCNK6(1) K2P16.1/KCNK16(1) K2P7.1/KCNK7(0) K2P17.1/KCNK17(0) K2P18.1/KCNK18(0) Kv1.1/KCNA1(18), Kv1.2/KCNA2(0), Kv1.3/KCNA3(0), Kv1.4/KCNA4(1), Kv1.5/KCNA5(0) Kv2.1/KCNB1(1), Kv2.2/KCNB2(0), Kv1.6/KCNA6(1), Kv1.7/KCNA7(0), Kv1.8/KCNA10(0) Kv3.1/KCNC1(1), Kv3.2/KCNC2(0), Kv3.3/KCNC3(3), Kv3.4/KCNC4(1) Kv4.1/KCND1(0), Kv4.2/KCND2(3), Kv4.3/KCND3(1) Kv5.1/KCNF1(1) 6TM, K , KCNX v Kv6.1/KCNG1(0), Kv6.2/KCNG2(0), Kv6.3/KCNG3(0), Kv6.4/KCNG4(0) K 7.1/KCNQ1 , K 7.2/KCNQ2 , K 7.3/KCNQ3 , K 7.4/KCNQ4 , K 7.5/KCNQ5 α v (26) v (139) v (93) v (11) v (7) Kv8.1/KCNV1(1), Kv8.2/KCNV2(2) α α K 9.1/KCNS1 , K 9.2/KCNS2 , K 9.3/KCNS3 v (0) v (0) v (0) I α Kv10.1/KCNH1(2), Kv10.2/KCNH5(2) Kv11.1/KCNH2(11), Kv11.2/KCNH6(3), Kv11.3/KCNH7(1) V Kv12.1/KCNH8(0), Kv12.2/KCNH3(1), Kv12.3/KCNH4(0) www.perspectivesinmedicine.org KCa1.1/BK/KCNMA1(3) KCa2.1/SK1/KCNN1(0), KCa2.2/SK2/KCNN2(2), KCa2.3/SK3/KCNN3(3) KCa3.1/IK/KCNN4(2) KCa4.1/slack/KCNT1(13), KCa4.2/slick/KCNT2(0) KCa5.1/KCNU1(0) Figure 1.
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